Varacin

Benzopentathiepins are stable solids. Varacin, a cytotoxic metabolite, was isolated from a marine ascidian.398 The parent benzopentathiepin exhibits infrared absorptions at 1620, 1570, 1235 and 1020 cm" 1.399 X-ray structure analyses of benzopentathiepin and 6-methylbenzopen-talhicpin show that the seven-membered ring in both compounds is nonplanar and that it adopts a chair conformation. The S-S bond lengths are in the range 204-206 pm.400... 

Essentially, this method was used for the various syntheses of varacin 433 435... 

Polycitor sp., Ascid, Tunicata varacin (aomatic polysulfide)/antimiaobial Makaieva 1995A... 

Varacin (114), a cytotoxic compound closely related to lissoclinotoxin A (106), was isolated from a Fijian sample of L vareau and a benzopentathiepin structure was proposed on the basis of spectral data [131]. Two total syntheses of varacin (114) have been carried out [132,133] and later, further syntheses were described [134-135]. N,N-dimethyl-5-(methylthio)varacin (115) and the corresponding trithiane (116) were obtained from L. japonicum from Palau and 3,4-desmethylvaracin (117) was isolated from a Eudistoma sp. from Pohnpei [136], An inseparable mixture of 5-(methylthio)varacin (118) and the corresponding trithiane (119) was obtained from a Pohnpeian Lissoclinum sp. [136]. Three additional antimicrobial polysulfides of the varacin family (120-122) were isolated from Polycitor sp., collected by dredging in the Sea of Japan [137]. 

A synthesis of varacin, a cytotoxic naturally occurring benzopentathiepin isolated from a marine ascidian and the total synthesis of the novel benzopentathiepin varacinium trifluoroacetate the viability of varacin free base was reviewed <1994MI242>. 

The structure of varacin was accomplished by complete spectral characterization of two derivatives (Section 13.17.7.14.2), including an X-ray diffraction analysis of (trimethylsilyl)ethoxycarbonyl (TEOC)-protected varacin 10 (Figure 13) <1994JOC5955>. The pentathiepin ring exists in the expected chair conformation. 

The ascidian Lissoclinum japonicum from Palau contained the antimicrobial and antifungal metabolites N,N-dimethyl-5-(methylthio)varacin and 3,4-dimethoxy-6-(2 -iV,./V-dimethylaminoethyl)-5-(methylthio)benzotrithiane, both of which were isolated as the trifluoroacetate salts <1994T12785>. They selectively inhibit protein kinase. Also, varacin and three new antimicrobial marine polysulfides, varacins A-C, were isolated from the Far Eastern ascidian Polycitor sp. <1995JNP254>, extracted from the New Zealand ascidian Lissoclinum notti <2002T9779>. 

A new route to the synthesis of the benzopentathiepin varacin 95 in six steps from 3,4-dimethoxyphenethylamine with an overall yield of 18% was described in 1995 (Scheme 18). The synthetic sequence includes novel thiocyana-tion and ligand-exchange steps, as well as an important modification in the pentathiepin construction step <1995JA7261>. 

Efficient synthesis of 6,7-dimethoxybenzopentathiepin 102 and 6-(2-aminoethyl)benzopentathiepin 103 (Figure 29), which are sectional structures of varacin, were proposed from 1,2-dimethoxybenzene and 1,2-benzene-dithiol, respectively <1995H(41)893>. 

Seven-membered rings with four and more heteroatoms attract attention because of their biological activity. An important class of compounds is that of the seven-membered cyclic polysulfides with five sulfur atoms, which are well known as lenthionine and varacin. 

Interest continues to be shown in the naturally occurring benzopentathiepine, varacin, in view of its cytotoxicity [01JA10379]. Analogues have also been made, for example, 319, by reaction of the dithiol, 3 17, with S g, and subsequent removal of the Boc protecting group from 318 [01H145],... 

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